Targeted therapies have shown great promise in the treatment of cancer. High-throughput screening (HTS) campaigns have often relied on assays using labeled ligands or enzyme substrates. Artifacts associated with labeling have led to the erroneous identification of compounds that act in on the labeled substrate rather than the intended target. A label-free, solution-based HTS method will facilitate identification of compounds acting specifically on the intended targets. The goal of this proposed research is to develop a spectro-optical calorimetry technology that will enable the use of calorimetry in high-throughput screening of compound libraries against cancer therapeutic targets. To achieve this goal, a thermochromic material, which converts temperature differences to absorbance wavelength changes will be selected, a microfluidic device to generate reaction droplets and provide rapid mixing of reactants will be fabricated, an optical detection system capable of detecting temperature changes in 500 pl reactions will be built, and the technique will be validated by measuring a suite of well-characterized reactions. The method will be demonstrated by measuring the binding to and inhibition of histone deacetylases 1 and 6 by known inhibitors. The spectro-optical calorimetry technology will enable full thermodynamic characterization of binding and enzymatic reactions with significantly better than the throughput of 1536-well plate assays when accounting for the need for labeled HTS assay development for new targets. The combination of higher throughput and lower sample consumption will change the way researchers view calorimetry: rather than being seen as a technique for a limited number of high-value measurements, it will be viewed as a primary screening method.